In mammals, micturition (urination) is a complex process that requires the integrated actions of the bladder, its internal and external sphincters, the musculature of the pelvic floor, and neurological control over these muscles at three levels (in the bladder wall or sphincter itself, in the autonomic centers of the spinal cord, and in the central nervous system at the level of the pontine micturition center (PMC) in the brainstem (pons) under the control of cerebral cortex) (De Groat, Neurobiology of Incontinence, (Ciba Foundation Symposium 151:27, 1990). Micturition results from contraction of the detrusor muscle, which consists of interlacing smooth muscle fibers under parasympathetic autonomic control from the sacral spinal cord. A simple voiding reflex is formed by sensory nerves for pain, temperature, and distension that run from the bladder to the sacral cord. However, sensory tracts from the bladder also reach the PMC, resulting in the generation of nerve impulses that normally suppress the sacral spinal reflex arc controlling bladder emptying. Thus, normal micturition is initiated by voluntary suppression of cortical inhibition of the reflex arc and by relaxation of the muscles of the pelvic floor and the external sphincter. Finally, the detrusor muscle contracts and voiding occurs.
Abnormalities of lower urinary tract function, e.g., dysuria, incontinence, and enuresis, are common in the general population. Dysuria includes urinary frequency, nocturia, and urgency, and may be caused by cystitis, prostatitis or benign prostatic hypertrophy (BPH) (which affects about 70% of elderly males), or by neurological disorders. Incontinence syndromes include stress incontinence, urgency incontinence, and overflow incontinence. Enuresis refers to the involuntary passage of urine at night or during sleep.
Prior to the present invention, treatment of neuromuscular dysfunction of the lower urinary tract has involved administration of compounds that act directly on the bladder muscles, such as flavoxate, a spasmolytic drug (Ruffman, J. Int.Med.Res. 16:317, 1988) also active on the PMC (Guarneri et al., Drugs of Today 30:91, 1994), or anticholinergic compounds such as oxybutynin (Andersson, Drugs 35:477, 1988). The use of .alpha.1-adrenergic receptor antagonists for the treatment of BPH is also common but is based on a different mechanism of action. (Lepor, Urology, 42:483, 1993).
However, treatments that involve direct inhibition of the pelvic musculature (including the detrusor muscle) may have unwanted side effects such as incomplete voiding or accommodation paralysis, tachycardia and dry mouth (Andersson, Drugs 35:477, 1988). Thus, it would be preferable to utilize compounds that act via the peripheral or central nervous system to, for example, affect the sacral spinal reflex arc and/or the PMC inhibition pathways in a manner that restores normal functioning of the micturition mechanism.
Lecci et al. (J. Pharmacol.Exp. Therapeutics 262:181, 1992) describe the effects of the 5-HT.sub.1A receptor ligands 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190, reference Compound Q) on micturition reflexes in the anesthetized rat. 8-OH-DPAT (an agonist) stimulated the supra-spinal micturition reflex (SMR) originating from the PMC, while NAN-190 inhibited the SMR. The authors concluded that spinal and supraspinal 5-HT.sub.1A receptors modulate the SMR in this system. The present inventors and their coworkers, however, have found that the efficacy of NAN-190 and other 5-HT.sub.1A receptor ligands in inhibiting SMR is directly correlated to their relative binding affinities for the .alpha.1 adrenergic receptor, rather than to their affinities, if any, for the 5-HT.sub.1A receptor (Guarneri et al., XXVII Congresso Nazionale Della Societa Italiana Di Farmacologia, 1994, page 310), which called into question the relevance of 5-HT.sub.1A antagonistic activity for treatment of neuromuscular dysfunction of the lower urinary tract. Furthermore, since NAN-190 is considered a partial 5-HT.sub.1A receptor agonist rather than a complete or "true" antagonist, there was no basis for concluding that "true" 5-HT.sub.1A receptor antagonism would be important for treating neuromuscular dysfunction of the lower urinary tract. The present inventors postulated that coordinated pre-synaptic and post-synaptic 5-HT.sub.1A receptor antagonism (see below) is an effective means to treat urinary tract disorders.
Many classes of 5-HT receptors have been identified, including 5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, and 5-HT.sub.4. 5-HT.sub.1 receptors further comprise 5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1D, 5-HT.sub.1E, and 5-HT.sub.1F subtypes, and 5-HT.sub.2 receptors comprise 5-HT.sub.2A, 5-HT.sub.2B, and 5-HT.sub.2C subtypes (The RBI Handbook of Receptor Classification, Kebabian and Nemeyer, Eds., page 58-61 (1994), RBI). Additional related receptor families include 5-HT.sub.5A, 5-HT.sub.5B, 5-HT.sub.6 and 5-HT.sub.7 (Saxena, Pharmac. Ther. 66:339, (1995)).
With respect to the 5-HT.sub.1A receptor, at least two functionally distinct types of this receptor subtype have been identified, which are designated "pre-synaptic" (or somatodendritic) and "post-synaptic". Pre-synaptic receptors are present on 5-HT-producing neurons and are involved in autoregulation of 5-HT release; their activation causes physiological changes including hyperphagia, hypothermia (in the mouse), bradycardia and hypotension. Post-synaptic receptors are widely distributed throughout the mammalian brain and are coupled to potassium channels and adenylate cyclase; their activation leads to "5-HT behavioral syndrome", hypothermia (in the rat), and elevation of plasma corticotropin levels. Beyond the differences in their anatomical distribution and functioning, pre-synaptic and post-synaptic receptors can be distinguished by the differential activity profiles of different 5-HT.sub.1A receptor ligands. For example, full agonists such as 8-OH-DPAT and 5-carboxytryptamine have agonist activity on both pre-synaptic and post-synaptic receptors. By contrast, partial agonists such as buspirone, ipsapirone, spiroxantine, urapidil, NAN-190, and BMY 7378 have agonist activity on pre-synaptic receptors and antagonist activity on post-synaptic receptors. Finally, compounds such as those encompassed by the present invention, referred to as "true" 5-HT.sub.1A receptor antagonists, exhibit antagonistic activity on both pre-synaptic and post-synaptic receptors.